Dissertation
Ambivalent action of cyclic AMP on degeneration and regeneration of cochlear afferent synapses during and after excitotoxic trauma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2019
DOI: 10.17077/etd.005183
Abstract
The type 1 spiral ganglion neurons (SGNs) conduct sound information from the inner hair cells (IHCs) to the brainstem. These SGNs are susceptible to damage even at sound levels that do not induce any hair cell loss. This kind of damage to the SGN synapses cannot be diagnosed by traditional audiometric tools. Hence, this loss of SGN synapses is termed as ‘hidden hearing loss’. The main reason for this type of synapse loss is due to glutamate excitotoxicity. In the first part of our study, we look at the possible mechanism that could potentiate SGN synapse loss.
The SGN neuron activity is modulated by the efferent projection from the brainstem called the lateral olivocochlear efferent (LOC). The LOC can secrete a wide array of neurotransmitters and neuropeptides, of which, we selected calcitonin gene-related peptide (CGRP) and acetylcholine. These two neurotransmitters are the major excitatory neurotransmitters secreted by the LOC. The organotypic culture experiments show that the CGRP can exacerbate synapse loss induced by excitotoxic stimulus. This action of CGRP is through its secondary messenger cyclic AMP (cAMP). cAMP potentiates this synaptopathic response through its exchange protein activated by cAMP (EPAC) protein. The calcium imaging study shows a significant increase in the susceptibility of the SGNs to excitotoxic stimulus when cAMP analog is in the culture. The culture studies done using acetylcholine also showed an exacerbated loss of synapses even at mild excitotoxic stimulus. Our preliminary data show that the main pathway of acetylcholine induced exacerbation of synapse loss is through muscarinic receptors. This insight into the mechanism controlling synaptopathy is vital for discovery of prophylactic measures to mitigate SGN synapse loss and generate optimal therapies.
The second part of our study was to look at potential way to regenerate the lost SGN synapses. We looked at the role of cAMP in promoting synapse regeneration after excitotoxic damage. We show that, both cAMP and the drug that elevates intracellular cAMP, rolipram, also promotes synapse regeneration in vitro. The animal study using the moderate noise paradigm that induces SGN synapse damage showed that rolipram treated mice showed a significant increase in SGN synapse regeneration. The functionality of these SGN synapses were tested using auditory brainstem response (ABR). The rolipram treatment showed a significant recovery in ABR amplitude after 2 weeks of treatment when compared to the vehicle treated control. The rolipram is a more selective drug with less invasive mode of administration making it a drug with a tremendous translational potential.
Details
- Title: Subtitle
- Ambivalent action of cyclic AMP on degeneration and regeneration of cochlear afferent synapses during and after excitotoxic trauma
- Creators
- Sriram Hemachandran
- Contributors
- Steven Green (Advisor)Daniel Eberl (Committee Member)Bernd Fritzsch (Committee Member)Marlan Hansen (Committee Member)Amy Lee (Committee Member)Joshua Weiner (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biology
- Date degree season
- Autumn 2019
- DOI
- 10.17077/etd.005183
- Publisher
- University of Iowa
- Number of pages
- xiv, 94 pages
- Copyright
- Copyright 2019 Sriram Hemachandran
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 86-94).
- Public Abstract (ETD)
The cochlea in the inner ear converts sound waves into electrical signals and transmits it to the brain, where it is perceived as sound. The type 1 spiral ganglion neurons (SGNs) are the primary neurons that conduct sound information to the brain. The SGNs are susceptible to damage even at moderate noise levels. This damage to the SGNs cannot be diagnosed using conventional audiometric tools. The common manifestation of this hearing impairment is the difficulty in understanding complex sounds such as speech in noisy environments.
The purpose of this study is two-fold. First, to understand the mechanism behind noise-induced SGN damage and, second, to find a potential way to regenerate the damaged SGNs and their contacts in the inner ear. We studied two molecules that are secreted by the feedback system that modulates SGN activity, Calcitonin gene-related peptide, and acetylcholine. Our study reveals that these molecules potentiate the damage to the SGNs even at a low level of trauma. This understanding will help us develop prophylactic therapies to prevent SGN damage.
We looked at the regenerative properties of the drug rolipram. Rolipram showed a significant improvement in the inner ear functionality of mice that had SGN damage due to noise exposure. Rolipram, with its ease in administration and specificity, has tremendous translational potential in treating SGN damage.
- Academic Unit
- Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9983779697802771
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